This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this project, now completed, was to define the role played by a gene termed FXYD1 in the neuropathology of Rett syndrome (RTT). This syndrome is an X-linked neurodevelopmental disorder linked to heterozygous de novo mutations in the MECP2 gene. In the absence of MECP2, the FXYD1 gene is overexpressed in both humans and Mecp2-null mice. FXYD1 encodes a trans-membrane modulator of Na+, K+-ATPase activity. These and other observations suggest that FXYD1 is a MeCP2 target gene whose de-repression may directly contribute to RTT neuropathogenesis. The results obtained indicate that decreasing FXYD1 expression by genetic means rescues learning and memory defects seen in the absence of MECP2, in addition to morphological deficiencies affecting neurons of the frontal cortex.